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Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy is highly effective but is associated with frequent unfavorable side effects. There is no fully published study yet exploring the safety, efficacy and required treatment duration of interferon-free treatment of acute hepatitis C virus monoinfection. Preliminary reports suggested that ledipasvir/sofosbuvir therapy is effective in acute hepatitis C but relapses were reported in HIV-coinfected patients after 6 weeks of treatment. The German HepNet Acute HCV IV Study was designed as a single-arm, prospective multicenter pilot study to evaluate the efficacy and safety of treatment with sofosbuvir plus ledipasvir (SOF/LDV) for 6 weeks without ribavirin in patients with acute genotype 1 HCV monoinfection. We here report the final 24 weeks’ post-treatment results. Twenty patients were included by 10 centers (60% male, mean age 46?±?12 years; 11 patients HCV genotype 1a, 9 patients genotype 1b). The main risk factors for HCV infection were sexual transmission (n?=?11) and medical procedures/needle stick injuries (n?=?5). Median alanine aminotransferase (ALT) and median bilirubin levels before start of antiviral treatment were 225 U/l (range 32–2716) and 13.6?µmol/l (range 5.13–111), respectively. ALT levels rapidly declined during therapy and values normalized already by treatment weeks 2 in nine patients and by week 4 in 17 patients. HCV RNA was undetectable by the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v2.0 by weeks 2, 4 and 6 in eight, 13, and 20 patients, respectively. SVR-12 was 100% and 19 patients have completed FU-week 24 and all remained HCV-RNA negative. One patient was lost to follow-up at week 24 post treatment. Treatment for 6 weeks with LDV/SOF was well tolerated and highly effective in HCV genotype 1 monoinfected patients with acute hepatitis C. Virological response was durable after therapy for at least 24 weeks. A rapid improvement in biochemical disease activity was observed during therapy. Short-duration treatment of acute hepatitis C could prevent the spread of HCV in high-risk populations and may be cost-saving as compared with treatment of chronic hepatitis C. Katja Deterding: Lecturer fees and travel grants from Gilead, MSD/Merck and AbbVie

To estimate the cancer risk of HIV-infected patients in the HAART era with respect to a general reference population and to determine risk factors for malignancy. Long term (1996-2009) cancer incidence of the Bonn single centre HIV cohort was compared to the incidence of the reference population of Saarland using standardized incidence ratios (SIR). Poisson regression analysis was used to identify predictors of cancer risk. 1,476 patients entered the cohort, enabling 8,772 person years of observation. 121 tumours in 114 patients, 7 in-situ and 114 invasive cancers, were identified. Malignancies associated with infectious agents such as Kaposi sarcoma (SIRs: male: 5,683; female: 277), non-Hodgkin lymphoma (SIRs male: 35; female: 18), anal cancer (SIRs male: 88; female: 115) as well a cervical carcinoma (SIR female: 4) and Hodgkin's disease (SIR male: 39) and liver cancer (SIR male: 18) were substantially more frequent in HIV-infected patients than in the general population (p < 0.001, each), whereas all other types of cancer were not increased. Poisson regression identified HAART (incidence rate ratio IRR (95% CI): 0.28 (0.19-0.41), p < 0.001), CD4 count (IRR per 100 cells/μl increase: 0.66 (0.57-0.76), p < 0.001), hepatitis B (IRR: 2.15 (1.10-4.20), p = 0.046) and age (IRR per 10 year increase: 1.23 (1.03 - 1.46), p = 0.023) as independent predictors for the occurrence of any type of cancer. HAART and preserved CD4 cells preferentially reduce the risk of malignancies associated with oncogenic infections.

Progressive immunodeficiency associated with HIV-infection leads to a progressive course of liver disease in HIV/HCV-co-infected patients. Highly active antiretroviral therapy (HAART) efficiently restores and preserves immune functions and has recently been demonstrated to also result in reduced liver-related mortality in HIV/HCV-co-infected patients. To analyse differences in current liver fibrosis as a possible effect of HAART on fibrosis progression we assessed hepatic fibrosis by transient elastography in a cross-sectional comparison between HCV-mono-infected and HIV/HCV-co-infected patients presenting at our outpatient department in 2007. Overall, we did not find any difference in the distribution of liver stiffness between mono- (n = 84) and double-infected (n = 57) patients (14.4 kPa (10.8 - 18.2) versus 12.4 kPa (9.1 - 16.1), mean (95%-CI)). However, in the 8 HIV+ patients with CD4 counts < 200/μl liver stiffness was markedly greater (18.4 kPa (0.8 - 36.0)) than in HIV+ patients with preserved immunity (11.5 kPa (8.4 - 15.0)). These findings are in line with other data that show an improved prognosis of chronic hepatitis C in HIV+ patients under effective HAART, and may be a hint that fibrosis progression in well-treated HIV+ patients will no longer be different from that in HCV-mono-infected patients.

Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function. The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients [GFR 44.9 ± 9.9 mL/min/1.73 m2measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ± 0.42 mg/dL] were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d. At month 12 mean SCr (-0.3 ± 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ± 13.1 mL/min/1.73 m2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ± 22 mmHg (p = 0.03). Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Interferon-alpha (IFN-α) has potent pro-inflammatory and anti-viral functions. It exerts its effects by inducing intracellular proteins such as MxA. To analyse the role of intrahepatic interferon activation, IFN-α and MxA expression was studied by immunohistochemistry in explant livers of 20 patients with fulminant hepatic failure (FHF), 41 patients with chronic liver disease (CLD), and ten normal controls (NCs). In NCs only small numbers of Kupffer cells, but no hepatocytes, showed IFN-α and MxA expression. In contrast, significantly enhanced numbers of IFN-α- and MxA-positive Kupffer cells, along with small numbers of MxA-positive and larger numbers of IFN-α-positive lymphocytes, were found in CLD and in FHF. MxA protein was also expressed on hepatocytes and bile ducts in the vicinity of IFN-α-positive inflammatory infiltrates (hepatocytes: NCs: 0%, CLD: 8%, FHF: 68%; bile ducts: NCs: 19%, CLD: 46%, FHF: 83%). A significant correlation was found between the numbers of IFN-α- and MxA-positive cells (r=0.67, p&lt;0.001). Thus, large amounts of IFN-α are released in the livers of patients with FHF, which is likely to contribute to immune-mediated liver cell damage. Intrahepatic MxA expression corresponds to IFN-α produced particularly by infiltrating inflammatory cells, rather than by hepatocytes themselves. Copyright © 2001 John Wiley & Sons, Ltd.

To investigate diabetic alterations of small intestinal transit and bacterial growth, we performed hydrogen breath tests (10 g lactulose via duodenal tube at the ligament of Treitz), bacterial cultures, and determinations of unconjugated serum bile acids in 19 patients with long-standing diabetes and 7 healthy controls. Asymptomatic diabetics had a late rise in breath hydrogen, indicating prolonged jejunal-cecal transit (86 ± 10 min, p < 0.05) as an early pathogenic event. Rise in breath hydrogen in symptomatic diabetics (constipation: 50 ± 6 min; diarrhea: 41 ± 11 min) was not significantly different from controls (57 ± 8 min). Bacterial studies and increased unconjugated serum bile acids suggest bacterial overgrowth in some symptomatic diabetics. Bacterial overgrowth was associated more frequently (p < 0.05) with a rise in breath hydrogen before 45 min or after 75 min. Changes in the hydrogen breath test, bacterial growth, or unconjugated serum bile acids did not correlate with gastrointestinal symptoms of diabetes.

Background: Impaired gallbladder emptying is a pathogenetic factor in gallstone formation. To test whether gallbladder motility can be improved by high-dose cholecystokinin (CCK), gallbladder emptying was measured sonographically in 21 patients with cholesterol gallstone disease and 6 healthy controls. Methods: The effects of CCK infusions of 0.06 IDU/kgmin (group A, n = 11) and 0.12IDU/kg/min (group B, n = 10) were compared with the response to a standard CCK infusion (0.02 IDU/kg/min). Controls received CCK at all infusion rates. Results: The ejection fraction was smaller after CCK infusion of 0.06 IDU/kg/min than after the standard stimulus (group A, 52 ± 10 versus 64 ± 10%, p < 0.05; controls, 66 ± 10 versus 91 ± 3%, p < 0.05). After infusion of 0.12 IDU/kg/min CCK ejection fractions decreased even more (group B, 44 ± 16 versus 65 ± 12%, p < 0.05; controls, 54 ± 12 versus 91 ± 3%, p <0.05). High-dose CCK infusions shortened the ejection period markedly, whereas the ejection rate remained unaltered. Conclusions: High-dose CCK does not improve gallbladder motility but blocks the ejection process early, leading to reduced gallbladder emptying in gallstone patients and healthy subjects.

To determine whether extracorporeal shock-wave lithotripsy of gallbladder stones alters gallbladder motility, gallbladder contraction in response to intravenous cholecystokinin was investigated by ultrasound. Twenty-one patients with symptomatic gallstones were studied before and after shock-wave lithotripsy, 12 with and 9 without concomitant litholytic therapy (combination of ursodeoxycholic acid and chenodeoxycholic acid). Gallbladder emptying was significantly delayed and less complete in both groups of patients before shock-wave treatment (with bile salts: residual volume, 51% ± 10% and half-ejection time, 40 ± 5 min; without bile salts: residual volume, 46% ± 7%; half-ejection time, 30 ± 4 min) compared with healthy controls (residual volume, 15% ± 4%; half-ejection time, 18 ± 2 min). Gallbladder motility was not altered in either group 1 day and 1 yr after lithotripsy. The findings indicate (a) that extracorporeal shockwave lithotripsy has no immediate or long-term adverse effects on gallbladder motility and (b) that the defect of gallbladder motility associated with gallstone disease is not abolished by removal of the stone.

Overcoming hepatitis B virus infection essentially depends on the appropriate immune response of the infected host. Among the hepatitis B virus antigens, the core (HBcAg) and e (HBeAg) proteins appear highly immunogenic and induce important lymphocyte effector functions. In order to investigate the importance of HBcAg/HBeAg-specific T lymphocytes in patients with acute and chronic hepatitis B and to identify immunodominant epitopes within the HBcAg/HBeAg, CD4+ T-cell responses to hepatitis B virus-encoded HBcAg and HBcAg/HBeAg-derived peptides were studied in 49 patients with acute and 39 patients with chronic hepatitis B. The results show a frequent antigen-specific CD4+ T-cell activation during acute hepatitis B infection, a rare HBcAg/HBeAg-specific CD4+ T-cell response among HBeAg+ chronic carriers, and no response in patients with anti-HBe+ chronic hepatitis. An increasing CD4+ T-cell response to HBcAg/HBeAg coincides with loss of HBeAg and hepatitis B virus surface antigen (HBsAg). Functional analysis of peptide-specific CD4+ T-cell clones revealed a heterogeneous population with respect to lymphokine production. Epitope mapping within the HBcAg/HBeAg peptide defined amino acids (aa) 1 to 25 and aa 61 to 85, irrespective of the HLA haplotype, as the predominant CD4+ T-cell recognition sites. Other important sequences could be identified in the amino-terminal part of the protein, aa 21 to 45, aa 41 to 65, and aa 81 to 105. The immunodominant epitopes are expressed in both proteins, HBcAg and HBeAg. Our findings lead to the conclusion that activation of CD4+ T lymphocytes by HBcAg/HBeAg is a prerequisite for viral elimination, and further studies have to focus on the question of how to enhance or induce this type of T-cell response in chronic carriers. The immunodominant viral sequences identified may have relevance to synthetic vaccine design and to the use of peptide T-cell sites as immunotherapeutic agents in chronic infection.

Since a dysregulated synthesis of tumor necrosis factor alpha (TNF-alpha) may be involved in the pathogenesis of autoimmune diseases, it was of interest to precisely locate the recently reported NcoI restriction fragment length polymorphism (RFLP) of the TNF-alpha region. However, by mapping of 56.8 kb of overlapping cosmid clones and direct sequencing, we could localize the polymorphic NcoI restriction site within the first intron of the TNF-beta gene and not in the TNF-alpha gene. To study whether regulatory mechanisms are affected by this polymorphism, we analyzed the TNF-alpha/TNF-beta production of phytohemagglutinin-stimulated peripheral blood mononuclear cells of individuals homozygous for the TNF-beta NcoI RFLP by ELISA and concomitant Northern blot analysis. On days 2-4 after stimulation with mitogen, the TNFB*1 allele corresponding to a 5.3-kb NcoI fragment presented with a significantly higher TNF-beta response. A mRNA analysis demonstrated that higher protein levels of TNF-beta correlate also with increased amounts of TNF-beta transcripts. No allelic association was found in respect to TNF-alpha production. To further investigate a possible allelic influence on transcription, we determined the DNA sequence of 2 kb of the 5' portion of our cloned TNFB*2 allele and compared it with the available TNF-beta sequences. By computer-aided recognition motif search of DNA binding factors, we report putative binding sites conserved between mouse and man in the 5' flanking region as well as in intron 1 of the TNF-beta gene, found also in other cytokine promoter sequences. In addition, by polymerase chain reaction amplification and sequencing of 740 bp of the 5' part of TNF-beta of individuals typed homozygously for the NcoI RFLP, we could show that amino acid position 26 is conserved as asparagine in the TNFB*1 and as threonine in the TNFB*2 sequence. A previously reported, EcoRI RFLP in the 3' untranslated region of TNF-beta does not segregate with either of the two alleles. Thus, four TNFB alleles can be defined at the DNA level.

Giardiasis is a common infection, and many of its symptoms are similar to those of Crohn's disease. Despite a long discussion on the role of microbiologic agents in Crohn's disease, giardiasis has never been investigated. We studied giardiasis as assessed by the occurrence of cysts in 86 patients with Crohn's disease, in 82 patients with other gastrointestinal disease, and in 52 patients without gastrointestinal disease. In addition, in 20 patients with Crohn's disease the effects of metronidazole on giardiasis and disease activity were studied. Frequency of giardiasis was 61.6% in patients with Crohn's disease, 31.7% in patients with other gastrointestinal disease, and 5.8% in the control group (p < 0.01). Stool frequency, disease activity, and humoral signs of inflammation in patients with Crohn's disease showed no relationship o giardiasis. All but two patients treated with metronidazole became free of cysts. rohn's disease activity index decreased in 14 of 20 patients (p < 0.05). In conclusion, giardiasis is a common finding in patients with Crohn's disease. Treatment of giardiasis can, in individual cases of Crohn's disease, result in a quick recovery from symptoms of high disease activity.

GASTROENTEROLOGY 2000;118:807

In order to characterize intrahepatic cytokine production, the mRNA levels of interleukin (IL)2, −4, and −10 and interferon (IFN)-γ were semiquantitatively determined by reverse-transcription competitive polymerase chain reaction in liver specimens from patients with chronic hepatitis C (n = 23), chronic hepatitis B (n = 9), or primary biliary cirrhosis (n = 12) and normal liver (control) specimens (n = 12). IL-4 mRNA was undetectable. Similar IL-10 mRNA levels were detected in all samples studied, including the controls. Mean IFN-γ and IL-2 mRNA levelswere elevated in chronic inflammatory liver disease. IL-2 mRNA levels were similar in all 3 patient groups, but intrahepatic IFN-γ mRNA levels were significantly higher in chronic hepatitis C than in chronic hepatitis B or primary biliary cirrhosis patients. This predominance of IFN-γ may indicate a lower susceptibility of hepatitis C virus to the antiviral effects of this cytokine. The presence of IL-10 in normal liver may impair the induction of antiviral immune responses.